Trial Outcomes & Findings for Evaluation of Renal Function, Efficacy, and Safety When Switching From Tenofovir/Emtricitabine Plus a Protease Inhibitor/Ritonavir, to a Combination of Raltegravir (MK-0518) Plus Nevirapine Plus Lamivudine in HIV-1 Participants With Suppressed Viremia and Impaired Renal Function (MK-0518-284) (NCT NCT02116660)

NCT ID: NCT02116660

Last Updated: 2019-04-08

Results Overview

Glomerular Filtration Rate (eGFR) was estimated from the Modification of Diet in Renal Disease (MDRD)-6 equation. The MDRD-6 equation = 198 × \[serum creatinine(mg/dL)\]\^-0.858 × \[age\]-0.167 × \[0.822 if patient is female\] × \[1.178 if patient is black\] × \[serum urea nitrogen concentration (mg/dL)\]\^-0.293 × \[urine urea nitrogen excretion (g/d)\]\^0.249.

• Recruitment status: TERMINATED
• Study phase: PHASE2
• Target enrollment: 11 participants
• Primary outcome timeframe: Baseline and Week 48
• Results posted on: 2019-04-08

Participant Flow

Human immunodeficiency virus (HIV) infected adults with stable suppressed HIV-1 ribonucleic acid (RNA) from at least 12 months prior to the screening visit, and with a current stable anti-retroviral (ARV) regimen were enrolled in this trial.

Participant milestones

Measure	Raltegravir Plus Nevirapine Plus Lamivudine Raltegravir 400 mg orally twice daily for 96 weeks; plus nevirapine 200 mg orally once daily for 14 days followed by nevirapine 200 mg orally twice daily, plus lamivudine 150 mg orally twice daily for 96 weeks	Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine Tenofovir/emtricitabine 300/200 mg orally once daily plus 1) lopinavir/ritonavir 400/100 mg orally twice daily or 800/200 mg orally once daily, or 2) atazanavir/ritonavir 300/100 mg orally once daily, or 3) darunavir/ritonavir 800/100 mg orally once daily or 600/100 mg orally twice daily
Overall Study STARTED	6	5
Overall Study COMPLETED	4	1
Overall Study NOT COMPLETED	2	4

Reasons for withdrawal

Measure	Raltegravir Plus Nevirapine Plus Lamivudine Raltegravir 400 mg orally twice daily for 96 weeks; plus nevirapine 200 mg orally once daily for 14 days followed by nevirapine 200 mg orally twice daily, plus lamivudine 150 mg orally twice daily for 96 weeks	Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine Tenofovir/emtricitabine 300/200 mg orally once daily plus 1) lopinavir/ritonavir 400/100 mg orally twice daily or 800/200 mg orally once daily, or 2) atazanavir/ritonavir 300/100 mg orally once daily, or 3) darunavir/ritonavir 800/100 mg orally once daily or 600/100 mg orally twice daily
Overall Study Deteriorating renal function	0	1
Overall Study Adverse Event	1	1
Overall Study Withdrawal by Subject	0	2
Overall Study Organization reason	1	0

Baseline Characteristics

Data for eGFR at baseline were not determined for 1 participant in each treatment group.

Baseline characteristics by cohort

Measure	Raltegravir Plus Nevirapine Plus Lamivudine n=6 Participants Raltegravir 400 mg orally twice daily for 96 weeks; plus nevirapine 200 mg orally once daily for 14 days followed by nevirapine 200 mg orally twice daily, plus lamivudine 150 mg orally twice daily for 96 weeks	Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine n=5 Participants Tenofovir/emtricitabine 300/200 mg orally once daily plus 1) lopinavir/ritonavir 400/100 mg orally twice daily or 800/200 mg orally once daily, or 2) atazanavir/ritonavir 300/100 mg orally once daily, or 3) darunavir/ritonavir 800/100 mg orally once daily or 600/100 mg orally twice daily	Total n=11 Participants Total of all reporting groups
Age, Continuous	49.83 Years STANDARD_DEVIATION 6.21 • n=6 Participants	54.00 Years STANDARD_DEVIATION 5.92 • n=5 Participants	51.7 Years STANDARD_DEVIATION 6.2 • n=11 Participants
Sex: Female, Male Female	2 Participants n=6 Participants	2 Participants n=5 Participants	4 Participants n=11 Participants
Sex: Female, Male Male	4 Participants n=6 Participants	3 Participants n=5 Participants	7 Participants n=11 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=6 Participants	0 Participants n=5 Participants	0 Participants n=11 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=6 Participants	5 Participants n=5 Participants	11 Participants n=11 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=6 Participants	0 Participants n=5 Participants	0 Participants n=11 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=6 Participants	0 Participants n=5 Participants	0 Participants n=11 Participants
Race (NIH/OMB) Asian	0 Participants n=6 Participants	0 Participants n=5 Participants	0 Participants n=11 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=6 Participants	0 Participants n=5 Participants	0 Participants n=11 Participants
Race (NIH/OMB) Black or African American	0 Participants n=6 Participants	1 Participants n=5 Participants	1 Participants n=11 Participants
Race (NIH/OMB) White	6 Participants n=6 Participants	4 Participants n=5 Participants	10 Participants n=11 Participants
Race (NIH/OMB) More than one race	0 Participants n=6 Participants	0 Participants n=5 Participants	0 Participants n=11 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=6 Participants	0 Participants n=5 Participants	0 Participants n=11 Participants
Estimated Glomerular Filtration Rate (eGFR)	87.5 mL/min STANDARD_DEVIATION 7.32 • n=5 Participants • Data for eGFR at baseline were not determined for 1 participant in each treatment group.	87.7 mL/min STANDARD_DEVIATION 6.52 • n=4 Participants • Data for eGFR at baseline were not determined for 1 participant in each treatment group.	87.62 mL/min STANDARD_DEVIATION 6.54 • n=9 Participants • Data for eGFR at baseline were not determined for 1 participant in each treatment group.

PRIMARY outcome

Timeframe: Baseline and Week 48

Population: All randomized participants who received at least one dose of study medications and who had both a baseline assessment, and at least one post-baseline assessment.

Glomerular Filtration Rate (eGFR) was estimated from the Modification of Diet in Renal Disease (MDRD)-6 equation. The MDRD-6 equation = 198 × [serum creatinine(mg/dL)]^-0.858 × [age]-0.167 × [0.822 if patient is female] × [1.178 if patient is black] × [serum urea nitrogen concentration (mg/dL)]^-0.293 × [urine urea nitrogen excretion (g/d)]^0.249.

Outcome measures

Measure	Raltegravir Plus Nevirapine Plus Lamivudine n=5 Participants Raltegravir 400 mg orally twice daily for 96 weeks; plus nevirapine 200 mg orally once daily for 14 days followed by nevirapine 200 mg orally twice daily, plus lamivudine 150 mg orally twice daily for 96 weeks	Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine n=4 Participants Tenofovir/emtricitabine 300/200 mg orally once daily plus 1) lopinavir/ritonavir 400/100 mg orally twice daily or 800/200 mg orally once daily, or 2) atazanavir/ritonavir 300/100 mg orally once daily, or 3) darunavir/ritonavir 800/100 mg orally once daily or 600/100 mg orally twice daily
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)	-1.1 mL/min Standard Deviation 4.65	-5.5 mL/min Standard Deviation 11.78

SECONDARY outcome

Timeframe: Week 48

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Plasma was to be collected at Week 48 in order to quantify HIV-1 RNA. and identify the percentage of participants with <50 copies/mL HIV-1 RNA.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Plasma was to be collected at Week 96 in order to quantify HIV-1 RNA. and identify the percentage of participants with <50 copies/mL HIV-1 RNA.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 48

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Plasma was to be collected up to Week 96 in order to quantify HIV-1 RNA, and identify the percentage of participants with >50 copies/mL HIV-1 RNA.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Plasma was to be collected at baseline and Week 96 in order to determine the change from baseline in HIV-1 RNA.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Participants were to be identified with mutations associated with Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTIs), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Integrase Inhibitor (INI). Virological failure is defined as 2 consecutive plasma HIV-1 RNA >200 copies/mL at least two weeks apart while on previous or current ARV therapy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Cluster of Differentiation 4 + (CD4+) T-lymphocyte cell counts were to be determined at baseline and Week 96, in order to determine the change from baseline.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Values of liver enzymes and lipids were to be determined from laboratory tests, in order to identify the percentage of participants classified with altered values.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Values of tubular kidney injury markers. were to be determined, in order to identify the percentage of participants classified with altered values.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and up to Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Changes from baseline in metabolic bone markers, serum Bone Specific Alkaline Phosphatase (s-BSAP) and C-telopeptides of type 1 Collagen (s-CTx), were to be determined, in order to classify the percentage of participants with changes.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Week 12: Fasted state (0 h) and 1, 2, 3, 6 and 12 h post-dose

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Blood samples were to be collected in Week 12 in order to use the trapezoidal method to determine the AUC0-t of Raltegravir and Nevirapine

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Weeks 12 and 48: at the end of dosing interval at 12 h

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Blood samples were to be collected in Weeks 12 and 48 in order to use the trapezoidal method to determine the Ctrough, the lowest concentration reached by the drug before the next dose is administered, of Raltegravir and Nevirapine.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Genotypic resistance measures the presence of particular HIV-1 mutations that give rise to drug resistance. Virological failure is defined as 2 consecutive plasma HIV-1 RNA >200 copies/mL at least two weeks apart while on previous or current ARV therapy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

An Adherence Questionnaire was to be given in order to determine the percentage of participants who adhered to study therapy.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Bone disease risk assessment was to be based on a Fracture Risk Assessment Tool (FRAX®) score in participants > 40 years old, and the change from baseline determined.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

The Veterans Aging Cohort Risk Index (VACS Index) combines various clinical biomarkers into a cumulative index weighted according to the risk of all-cause mortality.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Decline in renal function was to be assessed by evaluating MDRD-6, creatinine clearance and serum phosphate.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Week 96

Population: Due to poor enrollment the study was terminated early; therefore data for secondary outcome measures were not collected, and were not analyzed.

Glomerular Filtration Rate (eGFR) was estimated from the Modification of Diet in Renal Disease (MDRD)-6 equation. The MDRD-6 equation = 198 × [serum creatinine(mg/dL)]^-0.858 × [age]-0.167 × [0.822 if patient is female] × [1.178 if patient is black] × [serum urea nitrogen concentration (mg/dL)]^-0.293 × [urine urea nitrogen excretion (g/d)]^0.249.

Outcome measures

Outcome data not reported

Adverse Events

Raltegravir Plus Nevirapine Plus Lamivudine

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Measure	Raltegravir Plus Nevirapine Plus Lamivudine n=6 participants at risk Raltegravir 400 mg orally twice daily for 96 weeks; plus nevirapine 200 mg orally once daily for 14 days followed by nevirapine 200 mg orally twice daily, plus lamivudine 150 mg orally twice daily for 96 weeks	Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine n=5 participants at risk Tenofovir/emtricitabine 300/200 mg orally once daily plus 1) lopinavir/ritonavir 400/100 mg orally twice daily or 800/200 mg orally once daily, or 2) atazanavir/ritonavir 300/100 mg orally once daily, or 3) darunavir/ritonavir 800/100 mg orally once daily or 600/100 mg orally twice daily
Cardiac disorders Myocardial infarction	0.00% 0/6 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	20.0% 1/5 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.

Other adverse events

Measure	Raltegravir Plus Nevirapine Plus Lamivudine n=6 participants at risk Raltegravir 400 mg orally twice daily for 96 weeks; plus nevirapine 200 mg orally once daily for 14 days followed by nevirapine 200 mg orally twice daily, plus lamivudine 150 mg orally twice daily for 96 weeks	Protease Inhibitor/Ritonavir Plus Tenofovir/Emtricitabine n=5 participants at risk Tenofovir/emtricitabine 300/200 mg orally once daily plus 1) lopinavir/ritonavir 400/100 mg orally twice daily or 800/200 mg orally once daily, or 2) atazanavir/ritonavir 300/100 mg orally once daily, or 3) darunavir/ritonavir 800/100 mg orally once daily or 600/100 mg orally twice daily
General disorders Pyrexia	16.7% 1/6 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	0.00% 0/5 • Up to Week 98 All randomized participants who received at least one dose of study treatment.
Infections and infestations Gonorrhoea	16.7% 1/6 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	0.00% 0/5 • Up to Week 98 All randomized participants who received at least one dose of study treatment.
Infections and infestations Herpes zoster	16.7% 1/6 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	0.00% 0/5 • Up to Week 98 All randomized participants who received at least one dose of study treatment.
Infections and infestations Influenza	16.7% 1/6 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	0.00% 0/5 • Up to Week 98 All randomized participants who received at least one dose of study treatment.
Infections and infestations Pharyngitis	16.7% 1/6 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	0.00% 0/5 • Up to Week 98 All randomized participants who received at least one dose of study treatment.
Investigations Alanine aminotransferase increased	16.7% 1/6 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	0.00% 0/5 • Up to Week 98 All randomized participants who received at least one dose of study treatment.
Investigations Aspartate aminotransferase increased	16.7% 1/6 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	0.00% 0/5 • Up to Week 98 All randomized participants who received at least one dose of study treatment.
Metabolism and nutrition disorders Hypophosphataemia	0.00% 0/6 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	40.0% 2/5 • Number of events 2 • Up to Week 98 All randomized participants who received at least one dose of study treatment.
Renal and urinary disorders Renal impairment	0.00% 0/6 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	20.0% 1/5 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.
Skin and subcutaneous tissue disorders Lichen planus	16.7% 1/6 • Number of events 1 • Up to Week 98 All randomized participants who received at least one dose of study treatment.	0.00% 0/5 • Up to Week 98 All randomized participants who received at least one dose of study treatment.

Additional Information

Senior Vice President,Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: ClinicalTrialsDisclosure@merck.com

Results disclosure agreements

• Principal investigator is a sponsor employee The investigator agrees to provide to the sponsor 45 days prior to submission for publication or presentation, review copies of abstracts or manuscripts for publication that report any results of the trial. The sponsor shall have the right to review and comment with respect to publications, abstracts, slides, and manuscripts and the right to review and comment on the data analysis and presentation.
• Publication restrictions are in place

Restriction type: OTHER